Premature labor remains the leading cause of perinatal mortality and morbidity. Infant mortality dramatically decreases with increased gestational age. The survival rate of prematurely born infants increases from 20% at 24 weeks to 94% at 30 weeks. Moreover the cost associated with the care of an infant born prematurely is extremely high. While many agents have been developed for the treatment of premature labor in the last 40 years, the incidence of pre-term births and low birth weight infants has remained relatively unchanged. Therefore there remains an unmet need for the development of a safe and effective treatment of preterm labor.
Tocolytic (uterine relaxing) agents currently in use include β2 adrenergic receptor agonists such as Ritodrine which is moderately effective in suppressing preterm labor, but it is associated with maternal hypotension, tachycardia, and metabolic side effects. Several other agents have been used to suppress premature labor, including other β2 adrenergic agonists (terbutaline, albuterol), magnesium sulfate, NSAIDs (indomethacin), and calcium channel blockers. The consensus is that none of these agents are very effective; there is no clinical evidence showing that these compounds can prolong gestation for more than 7 days (Johnson, Drugs, 45, 684-692 (1993)). Furthermore, their safety profile is not ideal. Adverse effects include respiratory depression and cardiac arrest (magnesium sulfate), hemodynamic effects (calcium channel blockers), premature closure of the ductus arteriosus and oligohydramnios (NSAIDs; prostaglandin synthase inhibitors). Therefore, there is an unmet need for safer and more efficacious agents for the treatment of preterm labor with better patient tolerability. Specific requirements with regard to safety include a product with no or low rates of tachycardia, limited anxiety, improved fetal safety, and few, if any, adverse cardiovascular effects.
One target of interest is the oxytocin receptor in the uterus, and a selective oxytocin receptor antagonist has been proposed as an ideal tocolytic agent. While the exact role of oxytocin (OT) in parturition has not been clearly defined, there is evidence strongly suggesting that it may play a critical role in the initiation and progression of labor in humans (Fuchs et al. Science 215, 1396-1398 (1982); Maggi et al. J. Clin. Endocrinol. Metab. 70, 1142-1154 (1990); Åkerlund, Reg. Pept. 45, 187-191 (1993); Åkerlund, Int. Congr. Symp. Semin. Ser., Progress in Endocrinology 3, 657-660 (1993); Åkerlund et al., in Oxytocin, Ed. R. Ivell and J. Russel, Plenum Press, New York, pp 595-600 (1995)). Preliminary clinical trials with oxytocin receptor antagonists support the notion that a blockade of OT receptors reduces uterine myometrial activity and delays the onset of labor (Åkerlund et al., Br. J. Obst. Gynaecol. 94, 1040-1044, (1987); Andersen et al., Am. J. Perinatol. 6, 196-199 (1989); Melin, Reg. Pept. 45, 285-288 (1993)). Thus, a selective oxytocin antagonist is expected to block the major effects of oxytocin exerted mainly on the uterus at term, and to be more efficacious than current therapies for the treatment of preterm labor. By virtue of its direct action on the receptors in the uterus an oxytocin antagonist is also expected to have fewer side effects and an improved safety profile.
The following prior art references describe peptidic oxytocin antagonists: Hruby et al., Structure-Activity Relationships of Neurohypophyseal Peptides, in The Peptides: Analysis, Synthesis and Biology; Udenfriend and Meienhofer Eds., Academic Press, New York, Vol. 8, 77-207 (1987); Pettibone et al., Endocrinology, 125, 217 (1989); Manning et al., Synthesis and Some Uses of Receptor-Specific Agonists and Antagonists of Vasopressin and Oxytocin, J. Recept. Res., 13, 195-214 (1993); Goodwin et al., Dose Ranging Study of the Oxytocin Antagonist Atosiban in the Treatment of Preterm Labor, Obstet. Gynecol., 88, 331-336 (1996). Peptidic oxytocin antagonists suffer from a lack of oral activity and many of these peptides are non-selective antagonists since they also exhibit vasopressin antagonist activity. Bock et al. [J. Med. Chem. 33, 2321 (1990)], Pettibone et al. [J. Pharm. Exp. Ther. 256, 304 (1991)], and Williams et al. [J. Med. Chem., 35, 3905 (1992)] have reported on potent hexapeptide oxytocin antagonists which also exhibit weak vasopressin antagonistic activity in binding to V1 and V2 receptors.
Various non-peptidic oxytocin antagonists and/or oxytocin/vasopressin (AVP) antagonists have recently been reported by Pettibone et al., Endocrinology, 125, 217 (1989); Yamamura et al., Science, 252, 572-574 (1991); Evans et al., J. Med. Chem., 35, 3919-3927 (1992); Pettibone et al., J. Pharmacol. Exp. Ther, 264, 308-314 (1992); Ohnishi et al., J. Clin. Pharmacol. 33, 230-238, (1993); Evans et al., J. Med. Chem. 36, 3993-4006 (1993); Pettibone et al., Drug Dev. Res. 30, 129-142 (1993); Freidinger et al., General Strategies in Peptidomimetic Design: Applications to Oxytocin Antagonists, in Perspect. Med. Chem. 179-193 (1993), Ed. B. Testa, Verlag, Basel, Switzerland; Serradeil-Legal, J. Clin. Invest, 92, 224-231 (1993); Williams et al., J. Med. Chem. 37, 565-571 (1994); Williams et al., Bioorg. Med. Chem. 2, 971-985 (1994); Yamamura et al., Br. J. Pharmacol., 105, 546-551 (1995); Pettibone et al., Advances in Experimental Medicine and Biology 395, 601-612 (1995); Williams et al., J. Med. Chem. 38, 4634-4636 (1995); Hobbs et al., Biorg. Med. Chem. Lett. 5, 119 (1995); Williams et al., Curr. Pharm. Des. 2, 41-58 (1996); Freidinger et al., Medicinal Research Reviews, 17, 1-16 (1997); Pettibone et al., Biochem. Soc. Trans. 25 (3), 1051-1057 (1997); Bell et al., J. Med. Chem. 41, 2146-2163 (1998); Kuo et al., Bioorg. Med. Chem. Lett. 8, 3081-3086 (1998); Williams et al., Biorg. Med. Chem. Lett. 9, 1311-1316 (1999).
Certain carbostyril derivatives and bicyclic azepines are disclosed as oxytocin and vasopressin antagonists by Ogawa et al. in WO 94/01113 (1994); benzoxazinones are disclosed as oxytocin and vasopressin receptor antagonists by Sparks et al. in WO 97/25992 (1997); Williams et al. disclose piperidine oxytocin and vasopressin receptor antagonists in WO 96/22775 (1996); Bock et al. disclose benzoxazinone and benzopyrimidinone piperidines useful as oxytocin and vasopressin receptor antagonists in U.S. Pat. No. 5,665,719 (1997); piperazines and spiropiperidines useful as oxytocin and vasopressin receptor antagonists are disclosed by Evans et al. in U.S, Pat. No. 5,670,509 (1997) and by Bock et al. in U.S. Pat. No. 5,756,504 (1998); Bell et al. disclose piperazine oxytocin receptor antagonists in UK Patent Application, GB 2 326 639 A (1998); Bell et al. disclose benzoxazinone and quinolinone oxytocin and vasopressin receptor antagonists in UK Patent Application GB 2 326 410 A (1998); Bell et al. disclose benzoxazinone oxytocin and vasopressin receptor antagonists in U.S. Pat. No. 5,756,497 (1998); Matsuhisa et al. disclose difluoro tetrahydrobenzazepine derivatives as oxytocin antagonists in WO 98/39325 (1998); (1998); Ogawa et al. disclose heterocyclic bisamides with vasopressin and oxytocin antagonist activity in U.S. Pat. No. 5,753,644 (1998); and Ogawa et al. disclose benzazepine derivatives with anti-vasopressin activity, oxytocin antagonistic activity and vasopressin agonist activity, useful as vasopressin antagonists, vasopressin agonists and oxytocin antagonists in WO 97/22591 (1997) and U.S. Pat. No. 6,096,736 (2000).
Trybulski et al. disclose 3-carboxamide derivatives of pyrrolobenzodiazepine bisamides with vasopressin antagonist activity in U.S. Pat. No. 5,880,122 (1999); bicyclic thienoazepines with vasopressin and oxytocin receptor antagonist activity are disclosed by Albright et al. in WO 96/22294 (1996) and U.S. Pat. No. 5,654,297 (1997); and tricyclic benzazepines with vasopressin and oxytocin receptor antagonist activity are disclosed by Albright et al. in U.S. Pat. No. 5,849,735 (1998).
Albright et al. broadly disclose tricyclic benzazepine vasopressin antagonists in WO 96/22282A1 (1996) possessing antagonistic activity at the V1 and/or V2 receptors and which exhibit in vivo vasopressin antagonistic activity, as well as antagonistic activity at the oxytocin receptors.
Venkatesan et al. broadly disclose tricyclic benzazepines with vasopressin and oxytocin antagonist activity in U.S. Pat. No. 5,521,173 (1996), WO 96/22292 (1996), and in U.S.
Selected compounds of the present invention have been found to behave as potent oxytocin antagonists by binding with high affinity and selectivity to the oxytocin receptors, thus preventing oxytocin from binding to its receptors and exerting its biological and pharmacologic effects in vivo. They can be useful for the treatment and/or prevention and/or suppression of preterm labor, for the suppression of term labor prior to a caesarian delivery, and to facilitate antinatal transport to a medical facility. The compounds of the present invention also can produce contraception in mammals given that oxytocin antagonists have been shown to inhibit the release of oxytocin-stimulated luteneizing hormone (LH) from pituitary cells (Rettori et al., Proc. Nat. Acad. Sci. U.S.A. 94, 2741-2744 (1997); Evans et al., J. Endocrinol., 122, 107-116 (1989); Robinson et al., J. Endocrinol. 125, 425-432 (1990)).
The oxytocin antagonists of the present invention have the ability to relax uterine contractions induced by oxytocin in mammals and thus can be also useful for the treatment of dysmenorrhea, a condition characterized by pain during menstruation (Åkerlund, Int. Congr. Symp. Semin. Ser., Progress in Endocrinology 3, 657-660 (1993); Åkerlund, Reg. Pept. 45, 187-191 (1993); Melin, Reg. Pept 45, 285-288 (1993)). Primary dysmenorrhea is associated with ovulatory cycles, and it is the most common complaint of gynecologic patients. Myometrial hypercontractility and decreased blood flow to the uterus are thought to be causative factors for for the symptoms of primary dysmenorrhea (Åkerlund, Acta Obstet. Gynecol. Scand. 66, 459-461 (1987). In particular, vasoconstriction of small uterine arteries by vasopressin and oxytocin is thought to produce tissue ischemia and pain (Jovanovic et al., Br. J. Pharmacol. 12, 1468-1474 (91997); Chen et al., Eur. J. Pharmacol. 376, 25-51 (1999)).
The administration of oxytocin receptor antagonists to farm animals after fertilization has been found to enhance fertility rates by blocking oxytocin induced luteolysis leading to embryonic loss (Hickey et al., WO 96/09824 A1 (1996), Sparks et al., WO 97/25992 A1 (1997); Sparks et al., U.S. Pat. No. 5,726,172 A (1998)). Thus, oxytocin receptor antagonists can be useful in farm animal husbandry to control timing of parturition and delivery of newborns resulting in enhanced survival rates. They can also be useful for the synchronization of estrus by preventing oxytocin induced corpus luteum regression and by delaying estrus (Okano, J. Reprod. Dev. 42 (Suppl.), 67-70 (1996)). Furthermore oxytocin receptor antagonists have been found to have a powerful effect in inhibiting oxytocin-induced milk ejection in dairy cows (Wellnitz et al., Journal of Dairy Research 66, 1-8 (1999)).
Oxytocin is also synthesized in the brain and released in the central nervous system. Recent studies have established the importance of central oxytocin in cognitive, affiliative, sexual and reproductive behavior, and in regulating feeding, grooming and response to stress in animals. Oxytocin may also influence normal behavior in humans. Modulators of oxytocin binding to its receptors in the central nervous system may be useful in the prevention and treatment of disfunctions of the oxytocin system, including obsessive compulsive disorder (OCD) and other neuropsychiatric disorders (Kovacs et al., Psychoneuroendocrinology 23, 945-962 (1998); McCarthy et al., U. K Mol. Med. Today 3, 269-275 (1997); Bohus, Peptidergic Neuron, [Int. Symp. Neurosecretion], 12th (1996), 267-277, Publ. Birkhauser, Basel, Switz.; Leckman et al., Psychoneuroendocrinology 19, 723-749 (1994)).
Compounds which act to competitively inhibit binding of vasopressin its receptors are useful in the treatment or prevention of state diseases involving vasopressin disorders in mammals, which include vasodilation and aquaresis (free-water diuresis), treating hypertension and inhibiting platelet aggregation. They are useful in the treatment of congestive heart failure, cirrhosis with ascites, and in the syndrome of inappropriate secretion of antiduretic hormone (SIADH). Furthermore, vasopressin receptor antagonists have been found to be useful in treating disturbances or illnesses of the inner ear, particularly those related to Meniere's disease (Zenner et al., WO 99/24051-A2 (1999)); and for the prevention and treatment of ocular circulatory disorders, particularly intraocular hypertension or glaucoma and vision disorders such as shortsightedness (Ogawa et al., WO 99/38533-A1 (1999)).